Urea derivatives have found use in a wide variety of areas, including the pharmaceutical industry. More explicitly, Matsuda, Med. Res. Reviews, 1994, 14, 271, reports a number of urea compounds as acyl CoA:cholesterol O-acyl transferase (ACAT) inhibitors useful for the treatment of atherosclerosis.
In general, the preparation of urea derivatives from amines is based on the use of toxic phosgene, thiophosgene, phosgene substitutes or carbonic acid derivatives such as carbonyldiimidazole and derivatives. The most widely used method has involved the use of isocyanates or isothiocyanates. However, the preparation of isocyanates or isothiocyanates usually involves the use of phosgene or thiophosgene.
Recently improved methods for the synthesis of isocyanate derivatives have been reported. U.S. Pat. No. 4,294,774 (Henson et al.), and Japanese patent JP 63-150,255 (Takano et al.) report several processes involving the aminolysis of alkylcarbamates. Very often, these processes require drastic reaction conditions (high temperature) such as in U.S. Pat. No. 3,161,676 (Adams et al.).
Recently, novel methods for the preparation of urea derivatives were described involving the treatment of an alkylcarbamate with a magnesium amide (Basha, A., Tetrahedron. Lett., 1988, 29, 2525)., the DMAP-catalyzed reaction of an amine with a tert-butyl carbamate (Knolker, H.-J.; Braxmeier, T.; Schlechtingen, G.; Synlett, 1996, 502; Angew. Chem. Int. Ed. Engl., 1995, 34, 2497), the deprotonation of N-Boc with a strong base and reaction of the isocyanate thus formed with an amine (Lamothe, M.; Perez, M.; Colovray-Gotteland, V.; Halazy, S.; Synlett, 1996, 507), the reaction of an unsymmetrical diaryl carbonate (Freer, R.; McKillop, A., Synth. Commun., 1996, 26, 331) or an S,S-dimethyl dithiocarbonate with an amine (Leung, M.-K.; Lai, J.-L.; Lau, K.-H.; Yu, H.-H., Hsiao, H.-J., J. Org. Chem., 1996, 61, 4175). These methods call for harsh conditions, long reaction times and occasionally a large excess of amine.